Pathway of Isoniazid Metabolism

1
Pathway of Isoniazid Metabolism
alpha-ketoglutaric hydrazone --1--gt INH --1--gt
pyruvic hydrazone indirect pw direct pw
2
3
AcINH acetylisoniazid INA isonicotinic
acid INAG isonicotinylglycine MAH
monoacetylhydrazine DAH diacetylhydrazine
1 condensation 2 acetylation 3 hydrolysis 4
conjugation
AcINH
3
INA
Hydrazine
MAH
4
2
INAG
DAH
Sarma GR, Immanuel C, Kailasam S, Narayana ASL,
Venkatesan P. Rifampin-induced release of
hydrazine from isoniazid. A possible cause of
hepatitis during treatment of tuberculosis with
regimens containing isoniazid and rifampin. Am
Rev Respir Dis 1986 133 1072-1075.
2
Rate of Isoniazid Inactivation - Mitchell

• Rate of INH degradation 6 hr after std test
  dose
• slow 0.8 or higher per ml serum
• intermediate 0.4
• rapid 0.2 or less

• Not related to age, sex
• Not influence by presence of pulmonary TB,
  silicosis, pulmonary emphysema, DM, renal
  insufficiency, hepatic cirrhosis

Mitchell RS, Bell JC. NEJM 1957
2571066. Quoted in Kongsamran S, Yongchaiyudth
P, Viriyavejakul A, Prijyanonda B. Proceeding of
the Meeting of the Eastern Regional Committee of
the IUAT Nov 1962, 128-135.
3
Isoniazid Inactivation among Different Population

• Rapid Intermediate ()
• Armstrong Peart (1)
• Non-Eskimo (284) 44
• Eskimo (216) 95
• Sunahara (2)
• Japanese (1808) 88.5
• Ryukyuan (124) 85.5
• Thai (108) 72.3
• Ainu (86) 87.2
• Korean (65) 89.2
• Harris (3)
• European descent (25) 56
• Japanese descent (24) 87.5

1 Armstrong AR, Peart HE. Am Rev Tuberc Respir
Dis 1960 81 588. 2 Sunahara S, et al. Science
1961 134 1530. (abstract) 3 Harris HW, et al.
Am Rev Tuberc Respir Dis 1958 78 948. Quoted in
Kongsamran S, Yongchaiyudth P, Viriyavejakul A,
Prijyanonda B. Proceeding of the Meeting of the
Eastern Regional Committee of the IUAT Nov 1962,
128-135.
4
Isoniazid Inactivation in Thai Medical
StudentsPreliminary report

• Setting - Siriraj hospital Medical School
• 144 medical students (Thai 65, Chinese 19, mixed
  60)
• INH 4 mg/kg -gt blood at 2, 6 hours -gt culture of
  H37Rv H sensitive
• Rapid Intermediate Slow
• TOTAL 63 (43.8) 71 (49.3) 10 (6.9)
• Thai 33 (50.8) 27 (41.7) 5 (7.7)
• Chinese 6 (31.6) 12 (62.2) 1 (6.2)
• Mixed 24 (40) 32 (53.3) 4 (6.7)
• Male 44 (41.5) 53 (50) 9 (8.6)
• Female 19 (50) 18 (47.3) 1 (2.7)

Kongsamran S, Yongchaiyudth P, Viriyavejakul A,
Prijyanonda B. Proceeding of the Meeting of the
Eastern Regional Committee of the IUAT Nov 1962,
128-135.
5
Rapid Acetylators

• Race
• Oriental gt90, Blacks 45, Whites 45
• 90 ????????????, USA ??????????????? 50
• ??????? slow 6.9
• Sex
• independent of sex

Kalow WP. Pharmacogenetics, heredity and the
response to drugs, W B Saunders Co.,
Philadelphia, Pa., 1962, p. 93. Quoted in
Kopanoff DE, Snider DE, Caras GJ.
Isoniazid-related hepatitis. Am Rev Respir Dis
1978 117 991-1001.
6
Toxicologic Pharmacologic Aspects of Rifampin

• Semisynthetic derivative of rifampicin-B produced
  by Streptomyces mediterranei
• 1963 Research Laboratories of Lepetit in Milan,
  Italy
• 1966 extensively studied in Western Europe
• 0.5 mmg/ml -gt inhibit M. tuberculosis
• easily achieved serum level since readily
  absorbed on an empty stomach
• single 600mg on empty stomach
• -gt blood level many times that needed to inhibit
  bacilli in vitro, maintain for 12-24 hours
• Chief metabolite desacetylated form, also
  active against M. tuberculosis, not as readily
  absorbed
• After GI absorption -gt disperse through liver -gt
  elimination through bile ducts
• Intestinal absorption is affected by presence of
  food, desacetylation
• no cross resistance with other anti-TB drugs
• relatively nontoxic

Radner DB. Toxicologic and pharmacologic aspects
of Rifampin. Chest 1973 64(2) 213-216.
7
Side Effects of Rifampin

• Infrequently
• hematologic leukopenia, eosinophilia,
  thrombocytopenia
• skin various forms of rashes including
  urticaria
• hypersensitivity rare
• CNS headache, drowsiness, sense of fatigue,
  dizziness
• GI (most frequent)
• seldom severe - nausea, epigastric distress,
  gaseous distention, diarrhea
• significant - jaundice
• elevated SGOT, bilirubin, alkaline
  phosphatase
• interference with bromsulphalein (BSP)

Radner DB. Toxicologic and pharmacologic aspects
of Rifampin. Chest 1973 64(2) 213-216.
8
Drug Interaction - Rifampin

• Hepatropic drugs (BSP, contrast media in
  cholecystography) - competition
• both IV -gt high R plasma level, both oral -gt
  reduced R plasma level
• Anticoagulant
• decrease in prothrombin time, 5-8 d after
  starting R -gt 5-7 d after R withdrawal
• PAS
• decrease R serum concentration
• PAS should be administered at 8-12 hours
  intervals after R

Radner DB. Toxicologic and pharmacologic aspects
of Rifampin. Chest 1973 64(2) 213-216.
9
Pyrazinamide

• Metabolite pyrazinoic acid, 5-hydroxypyrazinoic
  acid (1,2)
• ?????????????????????? tubule ??????????? uric
  acid
• -gt ?????????????? uric acid ?????
• ??????????????????????????? Z
• ASA, allopurinol, placebo --gt ASA
  ??????????????????????????

1 Dllavd GA, Haslam RM. Observation on the
reduction of the renal elimination of urate in
man caused by the administration of pyrazinamide.
Tubercle 1976 57 97-103. 2 Weiner IM, Tinker
JP. Pharmacology of pyrazinamide metabolic and
renal function studies related to the mechanism
of drug-induced urate retention. J Pharm Exp
Ther 1971 180 411-433. 3 Horsfall PAL, Plummer
J, Allan WGL, Girling DJ. Double blind
controlled comparison of aspirin, allopurinol and
placebo in the management of arthalgia during
pyrazinamide administration. Tubercle 1979 60
13-24. ?????? ????????? ????????, ???????
???????????? ????????????????????????????????????
????????????????????????????????????
???????????????????????? 2532 10(3)
141-148.
10
Adverse Effects of Anti-TB DrugsA prospective
study in Region 5 during 1988-1989

• Subject - N137, 15 yr or more, 12 HE or SHE, E
  15-25 mg/kg/d
• ADR 11, male 4
• Symptoms n Time
• blurred vision 11 M 5-12
• itching, rash 10 0-M12
• nausea, vomiting 3 M 3-11
• jaundice 1 M6
• Duangchan Rattanamalaya. Thai Com Dis J
  199117(4)250-255.

11
Adverse Effects of Anti-TB DrugsA prospective
study at ZTC 12 Yala during Feb. 1991 - Jan. 1992

• Time of reaction
• Initial phase Continuation phase
• 2HRZ/4HR (186) 143 (77) 43 (23)
• 2HRZE/4HR (23) 20 (87) 3 (13)
• Severity
• Mild Severe (change of regimen)
• 2HRZ/4HR (186) 184 (99) 2 (1)
• 2HRZE/4HR (23) 23 (100) 0 (0)
• Pannee Hassapak et al. Thai J Tuberc Chest Dis
  20015(1)65-69.

12
Adverse Effects of Anti-TB DrugsA comparative
study at ZTC 3 Chonburi during Jul.-Dec. 1992

• N 160, new, 2HRZ/4HR 2HRZ/2HR, HRZ (82) vs
  Rifater (78)
• ADR 1wk 1-2wk 3-4wk 5-6wk 7-8wk
• SDF 52/82 (63) 17 27 13 9 4
• FDC 46/78 (59) 18 11 14 15 6
• Skin NS GI joint liver CHANGE regimen
• SDF (93) 37 21 9 8 1 3
• FDC (74) 34 12 13 5 2 3

????????? ???????????, ?????????? ????????, ?????
????????. ????????????????????????????????????????
? 3 ???? ?????????????????????????????????????????
??????????? 3 ??????. ????????????????????????
2537 15(1) 27-39.
13
Adverse Effects of Anti-TB DrugsA study at ZTC 3
Chonburi in 1992 - Patient response Treatment
received

• N 160, new, 2HRZ/4HR or 2HRZ/2HR, HRZ (82) or
  Rifater (78)
• ADR 167 occasions skin 44, NS 21, GI 14,
  joint 8, liver 2
• Patient response (98)
• nothing 29 (30) - self care 50 (51)
• visit near-by doctor 14 (14) - stop come to
  ZTC 5 (5)
• Treatment received (98)
• advice only 33 (34) - advice symptomatic Rx
  65 (66)
• resolve, continue anti-TB drugs 56
  (57)
• split dose 3 (3)
• change regimen 6 (6)

????????? ???????????, ?????????? ????????, ?????
????????. ????????????????????????????????????????
? 3 ???? ?????????????????????????????????????????
??????????? 3 ??????. ????????????????????????
2537 15(1) 27-39.
14
Adverse Effects of Anti-TB DrugsA prospective
study at ZTC 3 Chonburi during Nov 1992 - Oct 1994

• N 403, new, 2HRZ/4HR or 2HRZ/2HR, interview at
  M1 M2 M3 M4
• ADR 307 occasions skin 34, GI 17, NS 14,
  joint 6, liver 1
• ADR 215 persons (53) -gt change regimen 12
  (6)
• Time 1wk 55, 1-2wk 19, 3-4wk 17, 5-6wk 7,
  7-8wk 2
• Factor ADR P-value
• sex Male 52, Female 56 gt.05
• age 15-24 40, 25-34 53, 35-44 45, lt.05
• 45-54 66, 55-64 59, 65-gt 59
• severity M 60, M- 50 lt.05

????????? ???????????, ?????????? ????????, ?????
????????. ????????????????????????????????????????
??????????????????????????????????????????????????
????????????? 3 ??????. ????????????????????????
2538 16(4) 263-273.
15
Adverse Effects of Anti-TB DrugsA prospective
study at Chest hospital during Apr 1994 - Nov 1995

• N 233-gt226, new SP, 2HRZE/4HR, SDF
• ADR82 persons skin 44, GI 22, joint 9, liver
  4, vision 4, NS 2
• Time (wk) 1-30, 2-37, 3-7, 4-11, 5-1, 6-2,
  7-4, 8-7
• ???????? ???????? ????????????? split dose
  ????????? E ?????????????
• ??????? 9 21 - -
  6
• ???????????? 7 4 1 1
  5
• ??? ?????????? 6 1 -
  - -
• ?????? - 2 - -
  -
• ????????? - - - -
  3
• ????? - - -
  3 -
• ???????? 1 7 2 -
  3

???? ?????????, ????? ????????????.
??????????????????????????????????????? 4 ????
???????? 2 ?????????????????????????????????????
6 ?????. ???????????????????????? 2539 17(2)
103-116.
16
Adverse Effects of Anti-TB DrugsA study at Chest
hospital during May - Dec 2000

• N 92, new SP, 2HRZE/4HR, SDF, DOT by FM
• ADR38 persons
• Minor 32 Major 6
• ??????? 13 - ?????? ????????? 2
• ????????????? ?????? 8 - ???????????? 2
• ???????? ??????? ?????????? 8 -
  ????????????????? 1
• ????????????????? 2 - ????????????? 1
• ?????????? 1

???????? ????????, ????? ??????????, ?????
????????????. ???????????????????????????????????
??????????????????????????? DOTS
????????????????????. ????????????????????????
2543 5(3) 7-26.
17
Adverse Effects of Anti-TB DrugsA study at
Nongwuasor hospital during 1991 - 1993

• N 70, ADR 11, M1 1, M2 2, M3 7, M6 1
• Factor ADR no ADR
• sex male 6 (16) 32
• female 5 (16) 27
• age -gt 60y 5 (10) 44
• 61y -gt 6 (29) 15
• regimen 2HRZE/4HR 3 (17) 15
• 2HRZ/4HR 4 (11) 32
• 2SHRZ/4HR 2 (18) 9
• 12HRZ 1 (33) 2
• 12HE 1 (50) 1

Srijariya S, Nitkamharn O. Bulletin of the
Department of Medical Services 199419(4)152-158.
18
Hepatitis
19
British Thoracic Society Guidelines 1998

• Known chronic liver disease Weekly .. 2 wk, two
  weekly .. 2 mo
• No pre-existing liver disease, normal preRx LFT
  not require regular monitoring
• fever, malaise, vomiting, jaundice, unexplained
  deterioration repeat LFT
• virological tests to exclude coexistent viral
  hepatitis
• ALT/AST
• lt 2 times repeat at 2wk, fallen -gt repeat only
  for symptoms, gt2 times -gt Mx
• 2 or more times weekly.. 2wk, two weekly until
  normal
• 5 times or bilirubin rise -gt stop HRZ
• not unwell, non-infectious -gt no Rx until LFT
  return to normal
• unwell, AFB -gt SE until normal LFT

20
British Thoracic Society Guidelines 1998

• Once LFT is normal -gt challenge H -gt R -gt Z
• H 50mg/d -gt -gt -gt 300mg/d, no reaction 2-3 d
• R 75mg/d -gt -gt -gt 300mg/d, -gt -gt -gt 450-600 mg
• Z 250mg/d -gt -gt -gt 1gm/d, -gt -gt -gt 1.5-2.0 gm
• If no reaction -gt continue std Rx, withdrawn
  alternative drugs
• If further rx -gt stop offending drug, use
  alternative regimen 2HRE/7HR
• If reactions occur in patients with DR -gt
  desensitization carried out under the cover of 2
  other anti-TB drugs to avoid the emergence of DR

21
???????????????????????????????????????
??.???????? ?????????????? ????????????????
?????????????? ?.?????

• P D Information Bulletin 19975(3)27-29
• P D Information Bulletin 19975(4)39-40

22
???????????????????????????????????????

• ????????????????? (hepatotoxicity) - steatosis,
  cholestasis, acute hepatitis, chronic hepatitis,
  cirrhosis
• ???? - direct toxicity, immunologic
• acute hepatitis - hepatocellular / cytolytic,
  cholestatic
• cytolytic
• asymptomatic liver enzyme ?????????????????
• symptomatic
• anicteric ???????? ??????? ???????
  ????????????????
• icteric ??????
• fulminant/subfulminant encephalopathy

23
Isoniazid

• INH alone
• 10 -gt serum transaminase ?????????,
  ????????????? 10 ??????????, ?????????????????????
  ????
• 1 -gt hepatitis, ????? 3 ???????? (1 ???????-
  ???? 12 ?????)
• 0.05-0.1 -gt fulminant hepatitis (5 ???
  hepatitis)
• ?????? - ???? gt50??, ???????, delayed onset,
  ?????????????????????????????, serum bilirubin
  gt350 micromol/L
• direct gt immunologic, INH -gt acetylisoniazid -gt
  acetylhydrazine
• stable metabolite diacetylhydrazine
• reactive metabolite cytochrome P450

24
Rifampicin

• ?????? GI intolerance, ????????????? interstitial
  nephritis
• hepatitis ????, ???????????? cholestatic,
  ????????????????? INH ???? ??????????????????????
  cytochrome P3503a ?????? (powerful inducer)

25
Pyrazinamide

• 20 -gt transaminase ?????????
• 10 -gt symptomatic hepatitis
• ?????? fulminant hepatitis
• hepatitis HRZ gt HR gt H, ???????????? Z 0.5, ?? Z
  2
• ????????????? ??????? gt30mg/kg, ??????
• ???? direct gt immunologic
• ??? ?????? ???? eosinophilia ????????

26
Second Line Drugs

• Thiacetazone gt18 -gt mild liver dysfunction
• Ofloxacin, Sparfloxacin, Levofloxacin 20-40 -gt
  liver enzyme ?????, ??????? -gt symptomatic
  hepatitis
• PAS 0.3 -gt ?????????, ????? 6 ??????????, ?? ???
  ???? eosinophilia ????????????????? immunologic
• Amikacin, Kanamycin ????????????????

27
??????????????????????????????????????????

• HR ??????????? (10-20), ????????
• HZ ???????????
• RZ ??????????????????????????? R
  ??????????????????????? Z
• HRZ
• early onset serum transaminase ????????????? ???
  ????? 15 ??????, ?????????? R ??????? H,
  ????????????
• late onset serum transaminase ????????????
  ??????? 1 ?????, ??????????????? Z,
  ???????????????

28
????????????????????

• ????????????????????????????????????????
  ???????????????????????? ????????????????????
• ?????????????????????????????? ???????????????????
  ?????? ???????????????????????????????????????????
  ??
• ???????????? liver enzyme ??????????????????

29
????????????????????????????????????????????????

• ??????? baseline, ??????????????????????????????
• ???? transaminase ????????
• 2 ?????????? ?? 2 ??????????
• 1 ?????????? ???????????????????? HRZ
• 1 ???????? ??????????????? HR
• transaminase ?????????
• lt3 ?????????? high normal -gt ????????,
  ???????????
• gt3 ???? ?????? high normal -gt ????????????? 3 ???
• ????????????????????? ????????????? Z

30
??????????????????????????????????????????
????????, ?????? ????????????

• ???????????????????????? 254018(1)47-52

31
???????????????????

• ?? Asymptomatic Hepatitis Fulminant hepatitis
• H 10-25 0.5-3 0.06
• R - 1.1-1.4 -
• HR 35 2.7 -
• Z 20 1.25 -
• (40-50mg/kg) (20-30mg/kg)

32
Isoniazid

• Hepatocellular 90, mixed 10
• 50 ?? 2 ????????, ?????? 10 ????????????? R
• ???????? 2 ????? ???? bilirubin gt 20mg/dl -gt
  ??????????????????
• dose dependent effect ????????
• ??????????? ???????????, ???????????,
  ???????????, ???????????, ?????, hepatitis B
  carrier status, liver enzyme ????????????????
• ?????????? ???????????? 50 ????????????, 30
  ????? 2 ????????????

33
Rifampicin

• ???????????????????????? H
• ?????? bilirubin ????????????????? 3 ??.?????????
  ???????????????????? 24 ??.?????????? ??????? R
  ???? competitive inhibition ????????? bilirubin
• ??????? cholestatic jaundice ???????? R

34
Pyrazinamide

• ????????????????????? Z ????????? HR
  ????????????????????????????????

35
?????????????????????????????????????

• ????????????? - ???????????????????????????,
  ??????????????? (?????????? ???????? ???????)
  ???????????????????????????
• ??????????/?????????????
• ??? LFT ???????????????
• ???? -gt ???????????????????
• ???????/??????????? -gt ??????????????? ????? 2
  ?????
• ??????????????????????????????

36
?????????????????????????????????????

• ?????????????????????????????????? hepatocellular
  ??????????????????????????????????????????????????
  ????????????, ?????????? cholestatic ???????????
  R ????
• ??????????????????????? H ??????? R, Z
  ????????????????????? ??????????????????????????
  ????????????????????
• ???????????????? - ???????????, SGOT/SGPT ??? gt3
  ????, bilirubin gt3mg.dl, synthetic failure
  (albumin ???, prothrombin time ???????) -gt
  ??????????????????
• ????????????????????????????? ????????????????????
  ??????????????????? LFT ???????????????????,
  ?????? fulminant hepatitis ??????????? H ????
  ????????? ??????????????????????? 3 ??? -gt ?? 3
  ??? ??????? ??????????????????
• ????????????????????? ????????????????????????????
  3 ???????????????????????????????????????????????
  ?????????????????????????????? ???????????????????
  ???? ??????????????????
• ???????????????? ???????????? 3 -gt
  ??????????????????????????????????????
  ?????????????????
• ????????????????????????????????????
  ??????????????????? ??????????????????????????????
  ??????????????????????????? ??????????????????????
  ???? ???? S, E, O

37
Challenge ?? ??????? LFT ????????????

• ?????????????, ??? LFT ??? 3 ?????????????????????
  
• H 50mg 1d -gt 100mg 1d -gt 200mg 1d -gt 300mg
  3d
• R 150mg 1d -gt 300mg 1d -gt 450mg 1d -gt 600mg
  3d
• Z 250mg 1d -gt 500mg 1d -gt 1000mg 1d -gt 1500mg

38
Special Management of DRPs in Tuberculosis

• ???? ????????????
• ??????????? 254220(3)142-156.

39
Re-introduction ????????????

• H 50mg 1d -gt 100mg 1d -gt 200mg 1d -gt 300mg 1d -gt
• R 150mg 1d -gt 300mg 1d -gt 450mg 1d -gt 600mg 1d -gt
• Z 250mg 1d -gt 500mg 1d -gt 1gm 1d -gt 1.5gm
• ??? LFT ??? 3 ???
• successful 93 ?????????? hepatotoxic

40
Desensitization

• ????? 1/10 ??????????? -gt ?????????? 10 ???
• ??????? desen. ??????????? 2 ????????
  ?????????????????????
• ?????? corticosteroids

41
????????????????????????

• ????? ??????, ????? ??????????????, ???????
  ???????????, ????? ???????????, ???????? ????????
• ??????????????? 254414(1)40-46.

42
??????????????????????

• ??????????????????????????? 10-25
• ????????? 3 ???????? 4-12, H 0.6, H not R
  1.6, HR 2.7
• ????
• H ??????? hydrolysis ??? hydrazine ???? toxic
  metabolite, ??????? oxidation ??? reactive
  metabolite, ??????? R ???? cytochrome P450
  ??????????
• R inducer, cholestasis (??????? uptake
  ?????????????? bilirubin), hypersensivitity
• H ?????????? 2-8wk, ?? cholestatic hep. ???? 10,
  ??????? -gt CAH 10
• R ?????????????????????????? H, dose related -
  cholestasis
• Z dose related 40-50mg/kg -gt transaminase ?????
  20, hepatitis 8
• 20-35mg/kg ?????????????????

43
Metabolism ??? INH
INH
1
3
Acetyl hydrazine
2
1
Diacetyl hydrazine (non-toxic metabolite)
Hydrazine (toxic metabolite)
Cytochrome P-450 (Reactive metabolite)
R
1 acetylation 2 oxidation 3 hydrolysis
44
??????????????????????????????

• ?????????????????
• metabolism, ???????????, ??????????, immune
• ???????? - ????????????? ??????????
• acetaminophen, CCl4
• Idiosyncratic - ????????????? ??????
• hypersensitivity (immunoallergic) halothane,
  dilantin
• metabolite dependent (toxic metabolites) INH,
  methyldopa

45
????????????????????????????????????????

• ???? lt35 ?? ???? lt0.3, gt50 ?? ???? 2.3
• ?????????????
• ??????????????, ????????????????
• ????????????, BMI ???
• ?????????????????????
• ????????

46
??????????????????????????????????????????????????
????????????

• ????????? - ?????????????????????? ????????, LFT
  ???????????????????
• transaminase lt3 ???? ??? 2HRE/7HR ???? 2SHRE/7HR
• transaminase gt3 ???? ??? 2SHE/16HE
• LFT ???? ????????? 2-4 ??????? (????????????
  ??????????? 61)
• ???????????? ?????????????????????????????????????
  ???????
• ???????????? ??? transaminase gt3 ????,
  ??????????????, ???????????
• LFT ??? 1-2 ?????????????
• bilirubin ?????????????? ???????????
  ????????????????????? bilirubin
  ?????????????????? R, ?????? gt 3mg/dl ????
  ?????-??????????? 2wk -gt ???? R
• 83.3 ???????? 1-2 wk, ?????? gt1 m, ??????
  fulminant hepatitis ??????????????? acute liver
  failure ?????????????

47
Re-challenge ???????? ????????????????????????????
?????????

• H 50mg/d 2d -gt 100mg 2d -gt 200mg 2d -gt 300mg
• R 75mg/d 2-3d -gt 300mg/d 2-3d -gt 450mg 2-3d -gt
  600mg
• Z 250mg/d 2-3d -gt 1gm/d 2-3d -gt 1.5gm/d 2-3d -gt
  2gm/d

48
????
49
????????????????????? Isoniazid

• ???????
• lt35 ?? ???? liver damage lt0.3
• gt50 ?? 2.3
• pregnant women
• chronic alcoholism, chronic liver disease
• malnutrition
• AIDS, Hepatitis B carrier Status
• Concomittent hepatotoxicity drugs
• ?????

50
Fatal Cases in Thailand

• Year Drug Used Sex-Age Onset Effects
• 1989 H R E F 58 3 wk submassive hepatic
  necrosis

51
Fatal Cases in one state in US

• During 1973-1986, N20, H or HE (1 case 6HR/6H),
  19 for prevention
• 20 deaths of hepatitis, 18 with pathologic tissue
  consistent with DH (massive hepatic necrosis,
  submassive hepatic necrosis)
• Age 5-73 yr, Female 16, 12/19 underlying
  condition / receive a substance associated with
  fatty liver changes.
• 11/13 presented after gt 8wk of Rx
• 6 definite delay in stopping H after patient
  presented (1-27 d)
• 10/20 management errors (continue in the presence
  of grossly abnormal liver tests, operate for
  biliary obstruction, take H 600mg)

Moulding TS, Redeker AG, Kanel GC. Twenty
Isoniazid-associated Deaths in One State. Am Rev
Respir Dis 1989 140 700-705.
52
Fatal case - Preventive Therapy in US

• M 53 R600mg (6.7mg/kg) Z1750mg (19mg/kg)
• onset on D33 --gt liver necrosis failure -gt
  die 3 days after admission
• severe hepatitis
• F 59 R600mg (7.2mg/kg) Z2000mg (24mg/kg)
• D2 sick, D17 eosinophil 157-gt510,
  malaise-aorexia-feverishness, D49 jaundice
  altered mental status

53
Fatal INH-Induced Hepatitis during
ChemoprophylaxisLiterature Review by Salpeter SR

• Cases Hepatotoxic Death Rate
• Published studies 20,212 0 0
• Unpublished data 182,285 2 0.001
• Older gt 35 yr 43,334 1 0.002
• TOTAL 202,497 2 0.001

54
Isoniazid-Related HepatitisA US Public Health
Service Cooperative Surveillance Study

• Setting Washington DC 1970, 21 health
  departments
• N13838 receive IPT --gt probable 92 (M44),
  possible 82 (M37)
• Age vs probable cases per 1,000
• lt20y 0, 20-34y 3, 35-49y 12, 50-64y 23, gt64
  8
• Race vs probable cases per 1,000 oriental 21.7,
  white 12.6, black 1.6
• Month of occurrence
• Probable 62 by M3, 5 after M8 - Possible 32
  22
• Hx of alcoholconsumption 8,517 and 96 of 174
  probable possible
• Probable daily drinker 26.51000, drinker
  14.11000
• Death 8 probable 7 --gt female 6 (black 5),
• took H 8-19 wk, death 5-36 d after
  discontinue H

Kopanoff DE, Snider DE, Caras GJ.
Isoniazid-related hepatitis. Am Rev Respir Dis
1978 117 991-1001.
55
Criteria to Classify Isoniazid-Related Hepatitis

• Probable
• SGOT gt or 250 Karmen units
• or SGOT lt250 Karmen units but SGPT gt or SGOT
• and negative HBsAg (if done)
• and other causes of hepatitis not apparent
• Possible
• SGOT lt 250 Karmen units
• SGOT gt or 250 Karmen units in presence of other
  causes of liver dis.
• SGOT gt or 250 Karmen units, but lacking other
  biochemical tests

Kopanoff DE, Snider DE, Caras GJ.
Isoniazid-related hepatitis. Am Rev Respir Dis
1978 117 991-1001.
56
Acetylator Phenotype

• Slow 11 of 317 -gt hepatitis
• Rapid 1 of 244 -gt hepatitis

Parthasarathy R, Sarma GR, Janardhanam B, et al.
Hepatic toxicity in South Indian patients during
treatment with short-course regimens containing
isoniazid, rifampin and pyrazunamide for
tuberculosis. Tubercle 1986 in Press. Quoted in
Sarma GR, Immanuel C, Kailasam S, Narayana ASL,
Venkatesan P. Rifampin-induced release of
hydrazine from isoniazid. A possible cause of
hepatitis during treatment of tuberculosis with
regimens containing isoniazid and rifampin. Am
Rev Respir Dis 1986 133 1072-1075.
57
Risk Factors for Hepatotoxicity in Asian
PopulationAcetylation phenotype study in Hong
Kong

• Subject active pulm. TB, newly started Rx or
  stopped Rx for 3 d largely due to intolerance, N
  116
• H 200mg .. 3 hours .. -gt HPLC, single blood
  sample
• acetyl isoniazid (AcINH) INH bimodal
  distribution, anti-mode at ratio 1.5
• using this antimode, 25 -gt slow acetylators
• 12 -gt liver dysfunction 50 in slow acetylators,
  22 in normal LFT (P 0.04 Mann-Whitney U test)
• Oriental population -gt predominantly have rapid
  acetylator phenotype
• liver dysfunction significantly higher in
  carriers of HBV (34.9 vs 9.4)
• HCV, HIV independent additive risk factors for
  liver toxicity.

WW Yew. Risk factors for hepatotoxicity during
anti-tuberculosis chemotherapy in Asian
populations. Int J Tuberc Lung Dis
20015(1)99-100.
58
Reported Incidence of Hepatotoxicity in
Controlled Trials

• HRZ regimen 0.6-3

Singapore Tuberculosis Service/British Medical
Research Council. Assessment of a daily combined
preparation of isoniazid, rifampicin, and
pyrazinamide in a controlled trial of three
6-month regimens for smear-positive pulmonary
tuberculosis. Am Rev Respir Dis 1991 143
707-712. Singapore Tuberculosis Service/British
Medical Research Council. Clinical trial of six
month and four month regimens of chemotherapy in
the treatment of pulmonary tuberculosis the
results up to 30 months. Tubercle 1981 62
95-102.
59
Hepatotoxicity in Singapore

• Setting TB National referral centre,
  retrospective review
• Cohort start Rx in 1998, N 1036
• Hepatitis 55 (5.3), median time of Dx 38 days
  (7-183), 80 during 2 mo, symptomatic 67,
  jaundice 32.7, admit 29, fatal 3 (all with Z)
• Risk factors (multivariate analysis)
• abnormal baseline transaminase/bilirubin OR 2.1
  (1.1-4.3), P 0.02
• age gt 60 OR 1.97 (1.14-3.34), P 0.01
• female OR 1.9 (1.07-3.4), P 0.02
• Re introduction of Rx 48, successfully completed
  45, median time of recovery (onset of
  hepatitis-reinstitution of Rx) 23 days (8-83)

Teleman MD, Chee CBE, Earnest A, Wang YT.
Hepatotoxicity of tuberculosis chemotherapy under
general programme conditions in Singapore. Int J
Tuberc Lung Dis 20026(8)699-705.
60
Grading of Hepatotoxicity

• Times of ULN of AST or ALT
• Grade 1 gt1 - 2.5
• Grade 2 2.5 - 5.0
• Grade 3 5.0 - 20.0
• Grade 4 gt 20.0

Lee AM, Mennone JZ, Jones RC, Paul WS. Risk
factors for hepatotoxicity associated with
rifampicin and pyrazinamide for the treatment of
latent tuberculosis infection experience from
three public health tuberculosis clinics. Int J
Tuberc Lung Dis 20026(11)995-1000
61
Grading of Hepatotoxicity

• Times of ULN of AST
• Mild lt 5
• Moderate 5-10
• Severe gt 10

American Thoracic Society/Centers for Disease
Control and Prevention/Infectious Diseases
Society of America Treatment of Tuberculosis.
American Journal of Respiratory and Critical Care
Medicine 2003167(4)603-662.
62
Hepatitis during Regimens Containing HR

• Isoniazid hydrolase hydrolyze H -gt isonicotinic
  acid (INA) hydrazine
• Hypothesis - isoniazid hydrolase is inducible,
  daily R could lead to increase in formation of
  hydrazine, particularly in slow acetylators
• 14 healthy volunteers (slow 6, rapid 8)
• INH 300mg --3d --gt AcINH 400mg OR AcINH 400mg
  --3d --gt INH 300mg
• 1 d after -gt R 600mg for 10 d
• 7 d and 10 d after -gt INH 300mg OR AcINH 400mg
• (INAINAG) AcINH SLOW RAPID
• INH 300mg .97 (.73-1.23) .76 (.62-1.05)
• INH 300mgR 600mg 1.44 (1.22-1.67) .. 48 .98
  (.74-1.40) .. 29
• AcINH 400mg .67 (.54-.86) .73 (.49-1.21)
• AcINH 400mgR 600mg .81 (.65-.98) ..
  21 .84 (.62-1.56) .. 15
• mean proportion of INH metabolized through direct
  pw SLOW RAPID
• after H 2.9 0.3
• after HR 6.2 2.5
• hydrazine formed 65 micromol after H, 130
  micromol when HR (SLOW)

Sarma GR, Immanuel C, Kailasam S, Narayana ASL,
Venkatesan P. Rifampin-induced release of
hydrazine from isoniazid. A possible cause of
hepatitis during treatment of tuberculosis with
regimens containing isoniazid and rifampin. Am
Rev Respir Dis 1986 133 1072-1075.
63
Clinical Hepatitis in Patients Taking Anti-TB
Drugs

• Drug Number of Studies Patients Clinical
  Hepatitis
• H 6 38,257 0.6
• H not R 10 2,053 1.6
• H R 19 6,155 2.7
• R not H 5 1,264 1.1

Steele MA, Burk RF, Des Prez RM. Toxic hepatitis
with isoniazid and rifampin a meta-analysis.
Chest 199199465-471.
64
Clinical Hepatitis in Patients Taking Anti-TB
Drugs

• Drug LFT Clinical Hepatitis
• H transaminase 10-20 0.6 (metaanalysis of 6
  studies)
• 0.1-0.15 (11,141 treating LTI)
• R bilirubin 0.6 nearly 0
• Z 1

American Thoracic Society/Centers for Disease
Control and Prevention/Infectious Diseases
Society of America Treatment of Tuberculosis.
American Journal of Respiratory and Critical Care
Medicine 2003167(4)603-662.
65
HR Induced Submassive Hepatic NecrosisA case
report - Chulalongkorn hospital

• Female, 58 yr, pulmonary TB M, no liver disease
• H 5 mg/kg/d, R 10 mg/kg/d, E 15 mg/kg/d, no
  intake of other drugs
• 3 wk -gt nausea, anorexia
• 6 wk -gt jaundice, abdominal pain, disorientation
  -gt admission
• TB/DB 3.7/2.4 SGOT/SGPT 6430/1590
  HBsAg neg
• 5 d after admission -gt died

Kasantikul V, Isoniazid-Rifampicin Induced
Submassive Hepatic Necrosis, J Med Assoc Thai
1989 72(1) 56-58.
66
Hepatitis in a patient with TB meningitisA
retrospective study in Siriraj hospital during
1979-1986

• N 116-gt97, hepatitis 17 (17.5)
• criteria
• SGOTgt100 u/L or SGPT gt100 u/L (gt 3 times of NL)
• SGOT / SGPT lt 3 times jaundice bilirubin 2.5
  mg/dl
• Time 1-2 wk 8, 2-4 wk 7, gt4 wk 2
• Treatment
• stop drug 13 R 10, Z 6, H 4 --gt LFT normal
• not stop 4
• 1 SGOT/SGPT not normal but no symptoms
• 1 SGOT/SGPT decreased, but increased jaundice -gt
  died
• 2 SGOT/SGPT high for a period, then normal

??????? ????????????, ?????? ??????????, ??????
???????????. ????????????????????????????????????
????????????????. ?????????? 253039(8)435-439.
67
Drug Induced Hepatitis in 2RZ for LTBI

• CDC report 21 severe DH, 17 deaths

Centers for Disease Control. Fatal and severe
hepatitis associated with rifampicin and
pyrazinamide for the treatment of latent
tuberculosis infection -New York and Georgia,
2000. MMWR Weekly 20, 200150(15) 289-291.
68
Risk Factors for Hepatotoxicity associated with
RZ Treatment of LTBI

• Setting 3 TB clinics in Chicago USA,
  retrospective review
• Apr 1999-Mar 2001, 18 yr -gt, 2RZ (15-20mg/kg/d)
  N 157, chart available 148
• Male 43, presumed recent infection 53, IDU 28,
  Immigration from TB endemic country 11, HIV 6
• Completed Rx 85 (57.4), Grade 3 or 4
  hepatotoxicity 14 (9.4), 12 symptomatic, 11 stop
  Rx, no fatal (HBV 1/11, HCV 1/13)
• Risk factors for hepatotoxicity (multivariate
  model)
• presumed recent infection OR 14.3 (1.8-115)
• female OR 4.1 (1.2-14.3)

Lee AM, Mennone JZ, Jones RC, Paul WS. Risk
factors for hepatotoxicity associated with
rifampicin and pyrazinamide for the treatment of
latent tuberculosis infection experience from
three public health tuberculosis clinics. Int J
Tuberc Lung Dis 20026(11)995-1000
69
Definition of Hepatotoxicity

• Times of ULN of ALT/AST Bilirubin
• (36UL/33UL) (24umol/L)
• gt3
• gt2 gtULN

Teleman MD, Chee CBE, Earnest A, Wang YT.
Hepatotoxicity of tuberculosis chemotherapy under
general programme conditions in Singapore. Int J
Tuberc Lung Dis 20026(8)699-705.
70
Management For Jaundice - Expert Opinion

• Question - pulmonary SP, HRZ 3rd week -gt jaundice
• BTTA trials of SCC -gt jaundice not always of
  serious import
• Patient feel well - LFT, continue drugs, review
  in 1 wk
• unchanged -gt review clinically BCM in a
  further wk
• malaise, fever, nausea -gt stop all 3 drugs until
  feel better
• 18 ET, 18 ST, 18 SE or
• challenge with std dose R for a week
• jaundice recur -gt 18HE
• no problem -gt 2-5 d drug free -gt challenge with
  std dose H for a week
• liver disturbance -gt 18RE
• no problem -gt 9HR
• maintenance therapy with any combinations other
  than HR must be extended to 18 mo.

Campbell IA. Any questions. Tubercle 1990
71149.
71
Management of Anti-TB Drug-induced
HepatotoxicityEvidence from a RCT

• Hepatitis recurred P value
• Group 1 (20) 0 (0) 0.021
• retreated with SHRE gradually increasing No.
  dosage
• D1 S1000E1500, D3 H100, D6 H200, D9 H300, D12
  R300, D18 R450
• Group 2 (25) 6 (24)
• retreated with H300R600Z1500E1500
• same dosage throughout
• K. Tahaoglu, G. Atac, et al. The management of
  anti-tuberculosis drug-induced hepatotoxicity.
  Int J Tuberc Lung Dis 20015(1)65-69.

72
Drug Challenging

• Rash R -gt H -gt E or Z
• Hepatitis R -gt H -gt Z

American Thoracic Society/Centers for Disease
Control and Prevention/Infectious Diseases
Society of America Treatment of Tuberculosis.
American Journal of Respiratory and Critical Care
Medicine 2003167(4)603-662.
73
Visual Effects
74
????????????????????????????????? E??????????
APR ??????? 2/44

• Gouty arthritis, peripheral neuritis, retrobulbar
  optic neuritis
• retrobulbar optic neuritis
• 15mg/kg/d 1, 25mg/kg/d 6, gt35mg/kg/d 15
• ???????????? 2 ????? ????????????????,???????
  premanent blindness ???
• ?????????? Zn depletion ???? ??? chelation
• ????????? WHO (1988-1990) ??? E 807 ??????
• abnormal vision 332, visual field defect 60,
  blindness 24
• ????????? ADR ????? (2527-2542)
• abnormal vision 12, optic neuritis 3,
  conjunctivitis 2, visual field defect 1,
  conjunctival discoloration 1

75
??????????????????????
76
???????????????????????????????????????????

• Setting ???. 10 ?????????
• ???? 2HRZ/4HR (109-gt88), ???? 2HRZE/4HRE ????
  2HRZC/4HRC (55-gt44)
• Z dose lt45kg 1.5gm, gt45kg 2.0gm
• uric acid at M0 M2
• ???? 5.5 (1.8-10.5) 10.4 (5.8-17.0) .. 95
• ???? 4.8 (2.0-8.5) 10.3 (5.0-17.0) .. 95
• ???? ?????/????????????? (30) 5.5 / 5.6 10.2 /
  10.8
• ???? ?????/????????????? (13) 4.7 / 4.9 10.9
  /9.2
• ???????????? ASA, NSAID ??????????
  ???????????????????

????????? ????????, ??????? ????????????
??????????????????????????????????????????????????
??????????????????????
???????????????????????? 2532 10(3)
141-148.
77
Streptomycin
78
??????????????????????? Streptomycin

• ??????? - ????? 1 (161) ??? 750mg/d, ????? 2
  (122) ??? 1gm/d, 5/wk -gt 2 m
• ??????? 85 (32) A35, B43, C3, D4
• 750mg 48 (33.3) 21 21 2 4
• 1gm 37 (30.3) 14 22 1 0
• ?????? 750mg - ??????? 1gm - ???????
• ??? ??? 34/111 (30.6) 24/93 (25.8)
• ???? 14/33 (42.4) 13/29 (44.8)
• ???? -gt 39 32/96 (33.3) 25/88 (28.4)
• 40 -gt 16/48 (33.3) 12/34 (35.3)
• ??????? -gt44 12/35 (34.3) 12/30 (40.0)
• 45-gt 36/109 (33.0) 25/92 (27.2)
• ????????? ????????????? 10 ???????

?????? ?????????????, ????? ??????????.
?????????????????????????????? Streptomycin
???????????????????????.
??????????????? 2529 12(1)
21-35.
79
??????????????????????????????? Streptomycin

• A ????? ?????????? ????????????????
• B ????????????? ?????? ?????????????
• C ????????????? ????????????? ????????????????
• D ????????????? ?????????? ?????????????????

?????? ?????????????, ????? ??????????.
?????????????????????????????? Streptomycin
???????????????????????.
??????????????? 2529 12(1)
21-35.
80
Isoniazid Desensitization - A case report

• 36 year-old woman, AFB, H300 R400 Z1500
  Ethionamide1000
• D12 developed erythema multiforms on face, trunk,
  extremities
• All drugs was discontinued -gt dexamathasone CPM
  -gt resolved
• Reinstitution of Z, H -gt erythematous rash
• Reinstitution of R, Et -gt generalized
  maculopapular eruption
• Gradually increasing dose of oral solution (50mg
  in 500 ml distilled water) and then tablets of H
• D1-14 0.1, 0.2, 0.3, 0.4, 0.6, 0.8, 1, 2, 4, 8,
  16, 32, 70, 120 ml
• D15-191/4 tab, D20-24 1/2 tab, D25-29 1 tab,
  D30-34 2 tab, D35 3 tab
• Final regimen S500 thrice weekly, H300, PAS 8000

?????? ????????????????, ????? ?????????????.
??????????????????????????????????????????????????
oral desensitization.
????????????????????????
253311(3)175-177.